Process for preparing 16-alkyl-delta9,11-pregnenes



United States Patent 3,083,215 PROCESS FQR PREPARING l-ALKYlL-APREGNENES Frank A. Cutler, Jr., Westiield, and Meyer Sletzinger,

North Piainfield, N.J., assignors to Merck & (30., Inc.,

Railway, N.J., a corporation of New Jersey No Drawing. Filed Jan. 30,1959, Ser. No. 790,041

5 Claims. (Cl. Zed-397.45)

This invention relates to a process for preparing 16- alkyl steroidcompounds and to valuable intermediates produced thereby. Moreparticularly it relates to a method for preparing16-alkyl-9(ll),l6-pregnadiene compounds which are valuable intermediatesin the preparation of highly active anti-inflammatory steroids, as, forexample, 9a-fluoro-1 1B, 17a,21-trihydroxy-l5-methyl-l,4-pregnadiene-3,20-dione.

Methods are known by which 160: or l6B-alkyl steroids may be prepared.However, the known methods involve the use of costly and dangerousreagents such as organic peracids and diazomethane. For example, in oneof the known methods for introducing a 17-hydroxyl substituent into a16-alkyl-20-keto steroid, the ZO-keto steroid is converted to theZO-enol acylate and the unsaturated enol acylate of the ZO-keto steroidis treated with an organic peracid, e.g. perbenzoic acid, to convert the17(20)- double bond into a 17(20)-epoxide which may be hydrolyzed toform a l7u-hydroxy-l6-alkyl-20-keto steroid. Other methods used in thepreparation of 16,8-alkyl steroids involves the treatment of al6-pregnen-20-one compound with a diazoalkane such as diazomethane andsubsequently, pyrolysis of the alkyleneazo compound formed. The reagentsdescribed are not only dangerous to employ, but very costly to prepareand, thus the method which avoids the use of either or both of thesereagents is very desirable.

It is an object of this invention to provide processes for thepreparation of 16-alkyl-l6-pregnene compounds which avoid the use of thecostly reagents previously employed. A further object is the provisionof a simple process for the preparation ofl6-alkyl-9(l1),16-pregnadiene' compounds. Such compounds may be used inthe preparation of 'either l6a-alkyl or 16,3-alkyl steroids. Otherobjects more specifically described will be apparent irom the detaileddescription of the invention which folows.

In accordance with our invention it has now been found that 3-hydroxy(or acyloxy)-l6-alkyl-9(11)-pregnen-20- one compounds or their 20-enolderivatives are brominated to produce the corresponding17-bromo-3-hydroxy (or acyloxy) -16-alkyl-9 l 1)-pregnen-20-onecompounds or 17,2l-dibromo-3-hydroxy (or acyloxy)-16-alkyl-9(l1)-pregnen-ZO-one compounds which are then dehydrobrominated to produce3-hydroxy -(or acyloxy)-16-alkyl-9(ll), 16-pregnadiene-20-one compounds.

The bromination of the 3-hydroxy (or acyloxy)-16-alkyl-9(ll)-pregnen-20-one compounds to produce the corresponding17-monobromo or 17,21-dibromo derivatives is ordinarily conducted bycontacting a solution of the steroid with a solution of bromine in thepresence of a strong acid catalyst. Solvents for the brominationreaction may be chlorinated hydrocarbons such as chloroform, acetic acidor mixtures of these with a lower alkanol such as methanol. The acidcatalyst may be any strong non-oxidizing acid which will not degrade thesteroid molecule. sulfonic acid, 3,S-dinitrobenzenesulfonic acid aresatisfactory for this purpose. The temperature of the bromination may bevaried between about 30 to 100 C. inclusive, although it is preferablymaintained at about 45 to 50 C. in order to effect the best yields ofbromo compound. When the 20-enol derivative is the compound Acids suchas hydrobromic acid, p-toluene ice brominated it is preferred to carryout the bromination in the presence of a tertiary amine using excessbromine.

When a molar ratio of about 2 moles of bromine to 1 mole of ZO-ketosteroid is employed the 17,2l-dibromo derivative results and when theZO-enol derivative of the ZO-keto steroid is brominated the 17-monobromosteroid is the compound isolated. Thus, when the ZO-enol de rivativesare employed as, for example, the ZO-magnesium enolate of3-acetoxy-16a-methyl-9*(ll),17(20)-pregnadine, the ZO-cadmium enolate of3-acetoxy-l6a-methyl- 9(l1),17(20)-pregnadiene and3,20-diacyloxy-1oer-methyl-9(1l),l7(20)-pregnadiene and are contactedwith excess bromine in an alkaline medium, the compound obtained onisolation is 3-acetoxy-16ot-methyl-17a-bromo- 9(1l)-pregnen-20-one. Whenthe steroid employed is the ZO-ketone, e. g. 3-acetoxy-l6oc-methyl-9( 1l -pregnen-20- one and a molar ratio of 2 moles of bromine to l ofsteroid is used the compound obtained after bromination and isolation is1701,2l-dibromo-S-acet-oxy-low-methyl- 9 l l -pregnen-20-one.

The second step of our process involves the treatment of a 17-bromosteroid, for example, a 17-bromo-3-hydroxy (oracyloxy)-l6-alkyl-9(ll)-pregnen-20 one or a 17,21-dibromo-3-hydroxy (oracyloxy)-l6-alkyl-9(1l)- pregnen-ZO-one with a dehydrobrominating agentto form the corresponding 9(11),16-pregnadiene compound. In the case ofthe 17-monobromo intermediate the compound is ordinarily contacted witha dehydrobrominating agent, e.g. a tertiary amine such as pyridine,lithium chloride in an N,N-diloweralkylamide such as dimethylformamide,or dimethylformamide alone, to form directly the3-acyloxy-16-alkyl-9-(l1)-pregnen-20-one. When this reaction is carriedout in the presence of a tertiary amine such as pyridine, it isordinarily conducted by maintaining the reaction mixture at the refluxtemperature for a period of several hours, following which the productmay be recovered by precipitation with Water and crystallization from anorganic solvent.

When the brominated intermediate employed is a 17, Zl-dibromo steroidas, for example, 17,21-dibromo-3-acetoxy-l6a-methyl-9(11)-pregnen-20-one, the preferred method ofdehydrobromination is to contact an organic solvent solution of thesteriod for a brief period of time with at least two moles of an alkalimetal iodide. The organic solvent employed is not critical and may be alower aliphatic ketone, a lower alkanol or mixtures thereof with anaromatic hydrocarbon, e.g. acetone, methanol and benzene. Uponcompletion of the reaction the formed sodium bromide, which arises as aby product, may be removed by filtration although it is not necessarilydesirable to do so, and the organic solvent is removed by evaporationunder vacuo, leaving a residue comprising as the principle component,3-acetoxy-l6ix-methyl-9(11),l6- pregnadiene-ZO-one with a small amountof the l7-bromo- 3-acetoxy-l6ot-methyl-9t1l)-pregnen-2()-one remainingas a byproduct of the reaction. The 17-monobromo may be converted to thedesired pregnadiene compound by a further treatment with a tertiaryamine as described in the preceding paragraph. The temperature at whichthe treatment with sodium iodide is effected is not critical and mayvary between about 40 C. and the reflux temperature of the reactionmixture, temperatures'ranging between about 49 to 60 C. beingpreferable.

Utilizing as the brominated steroid intermediate 17- bromo-3 -hydroxy-(or acyloxy) -16-alkyl-9 l 1 -pregnen- 20-one, e.g.17-bromo-3-acetoxy-l6u-methyl-9(11)-pregnen-ZO-one, the product obtainedis 3-acetoxy-l6-methyl- 9(1l),l6-pregnadien-20-one. When a l7,2l-dibromointermediate is contacted with sodium iodide, the corresponding 9(ll),l6-pregnadiene product is obtained as the major component. Thus,for example, when 17:4,21-dibromo-3-acetoxy-l6oc-methyl-9(1l)-pregnen 20one is contacted with sodium iodide the major product obtained is3-acetoxy-16-methyl-9 l l ,16-pregnadien-20-one associated with a smallamount of the byproduct, l7-br0m0- 3-acetoxy-16e-methyl-9(11)-pregnen-20-one which may be dehydrobrominated by subsequenttreatment with refluxing pyridine to produce '3-acetoXy-l6-methyl-9(1l),l6-pregnad-ien-20-one.

The following examples are intended to be illustrative of the inventionclaimed and therefore, the invention is not necessarily limited thereto.7

EXAMPLE 1 30c-A cetoxy-l 6-Methyl-9 (1 1 ),16-Pregnadien-20-One To asolution 1 g. (2.7 mm.) of 3ot-acetoxy-l6amethyl-9(l1)-pregnen-20-one in50 ml. of chloroform at 45-47 C. is added 13.7 ml. (5.4 mm.) of 0.395 Mbromine in chloroform over a period of 130 minutes. After a 15 minuteaging period the solution is cooled to room temperature, washed with 40ml. of sodium bicarbonate solution and two 75 ml. portions of water. Thesolution is dried over magnesium sulfate and evaporated. The residuecomprising the 17,21-di bromide is dissolved in 25 ml. of warm acetoneto which'l.5 g. sodium iodide has been added and allowed to stand atroom temperature for a half-hour. The mixture is filtered fromprecipitated sodium bromide and the filtrate is evaporated under reducedpressure and below 30 C. The residue is distributed between 25 ml. ofether and 25 ml. of 10% sodium bisulfite solution. The system is shakenintermittently until the iodine color fails to return to the etherphase. The ether phase is then washed with two 25 ml. portions of 2%sodium carbonate solution and two 50 ml. portions of Water. The ethersolution is dried over magnesium sulfate and evaporated, leaving aresidue comprising the 17-monobromide. The monobromide is disolved inml. of dry pyridine and heated at the reflux temperature for six hours.The solu tion is cooled, diluted with 75 ml. of water, and extractedwith three 50 ml. portions of chloroform. The combined chloroformextract is washed successively with 75 ml. of water, two 50 ml. portionsof dilute hydrochloric acid, two 50 ml. portions of 10% sodiumbicarbonate solution, and three 75 ml. portions of water. The chloroformsolution is evaporated'under reduced pressure leaving a residuecomprising 3a-acetoxy-16-methyl-9 (1 1),l6-pregnadien-ZO-one and showingthis bromination and dehydrobromination procedure'as,

for example, the propionate, the butyrate', 'the' benz'oate, theproducts obtained after bromination and dehydrobromination are thecorresponding propionates, :butyrates and benzoates. Other 16-alkyl,steroids, 3-acetoxy 16- ethyl-9(11)-pregnen-20-one, 3-acetoxy-l6-prop yl9(1 1)'- p'regnen-ZO-one and 3-acetoxy-16-butyl-9 1 l -pregnenone may betreated according to the above procedures to produce the corresponding17,21 dibr-omo-16 alkyl steroid and the l 6-alkyl-9(11),l6pregnadienesteroids.

7 7 EXAMPLE 2 3a-Acetoxy-l6-Methyl-9(11) ,I6-Pregnt1dien-20-0rte Asolution of. 3 ot-hydroxyl6-methyl-9 11) ,16-preg- 7 temperature for sixhours.

nadien-ZO-one in 1 ml. of pyridine and 1 ml. of acetic anhydride isheated 1 hour on the steam bath. The solution is then cooled and dilutedslowly with water to a volume of 10 ml. The resulting suspension ofcrystals is chilled and filtered. After washing with water and drying,the crude 3ot-ac'etoxy-16-methy1 9(11),16 pregnadien-ZO- one melted atl25l28.5. A 0.200 g. portion is recrystallized from 2 ml. of Skellysolve-B, yielding 0.175 g. of crystals, M.P. 128-130, showing li at 251 my,A% :225

EXAMPLE 3 1 ,21-Dibr0m0-3a-Aceroxy-16ot-MetIzyl-9 (l1 Pregnan- To asolution of 10 g. (0.027 mole) of3a-acetoxyl6u-methyl-9(11)-pregnen-20-one in ml. of chloroform at 4050is added 55 ml. (0.054 mole) of 0.98 M bromine-in-chloroform over aperiod of minutes. After a further aging period of 20 minutes, thesolution is cooled to room temperature and washed successively with 100ml. of 10% sodium bicarbonate solution and two 100 ml. portions ofwater. After drying over magnesium sulfate the chloroform solution isconcentrated to a syrup under reduced pressure. a The residue istriturated with 50 ml. of acetone and the resulting suspension ofcrystals of 17,21-dibromo-3a-acetoXy-l6a-methyl- 9(1l)-pregnen-20-one ischilled and filtered. The crystals after washing with cold acetone anddrying Weighed 7.58 g; MP. 196-205 (doe). A specimen crystallized threetimes further from acetone melted at 2162l9 (dec.).

EXAMPLE 4 3u-Acetoxy-l6-Methyl 9 (11 ,16-Pregnadien-20-One A solution of1 g. (1.9 mm.) of crude 17,21-dibromo- 3 u-acet0xy-l6e-metl1yl-9(l1)-pregnen-20-one prepared as in Example 3 and 1 g. of sodium iodide in25 ml. of

acetone is refluxed for two hours, developing an iodine color andprecipitating sodium bromide. The suspension is cooled to roomtemperature and filtered. The sodium bromide thus collected weighed 0.39g. (3.8 mm.). The filtrate is concentrated under reduced pressure andthe residue is distributed between 50 ml. of ether and 50 ml. of 10%sodium bisulfite solution to remove iodine. There is no return of iodinecolor in the organic phase as is usual when 21-iodo-20-ketosteroids arepresent. The ether phase is washed with two 50 ml. portions of 2% sodiumcarbonate solution and two 50 ml, portions of water. Drying of the ethersolution over magnesium sulfate and, evaporation gives crude3oz-acetoxy-16-methyl- 9(1l),l6-pregnadien-20-one,

kg? at 251 m A%=129 The material melted at 90-1 12 and darkened anddecomposed at 180400 suggesting the presence of traces of halogen. Theentire product (0. 72 g.) is therefore dissolved in 10 ml. of drypyridine and heated at the reflux V The solution is then cooled to roomtemperature and diluted with 50 ml. of water, yielding a suspension ofcrystals. After chilling, the crystals are collected, washed with water,and dried; M.P. 109-118 C;

PART 1.PREPARA'IION OF 3a,20-DIACETOXY-l6 METH YL 9.(11),17(20)-PREGNADIENE a A solution of '5 g. of 3u-acetoxy-l6 t-rnethyl-9(11)- pregnenQO-onein 50 ml. of acetic anhydride and 200 ml.

of toluene containing 0.5 g. of 2,4-dinitrobenzenesulfonic acid isheated at the reflux temperature for 17 hours. The solution is thencooled to room temperature and after removal of 38.6 ml. in samples, 1.0g. of potassium acetate is added. The mixture is concentrated to a syrupcomprising 3a,20 diacetoxy-16-methyl-9(11),17(20) pregnadiene. This isused directly in Part 2.

PART 2.PREPARATION OF 17-BROMO-3a- METHYL-9 (11) -PREGNEN-20 ON Afterremoval of a sample, the remainder of the enol acetate prepared in Part1 is dissolved in 78.2 ml. of glacial acetic acid and 11.7 ml. of drypyridine. To the solution at room temperature over a period of an houris added 20 ml. of 0.386 N bromine in acetic acid. Then water and icetotaling about 100 g. are added, giving a suspension of solid. This iscollected, washed, and dried and comprised 17 -bromo-3 a-acetoxy- 16ot-methyl-9 1 1 pregnen-ZO-one.

CETOXY-lGa- E PART 3DEHYDROBROMINATION A solution of 1.0 g. of productprepared in Part 2 in 10 ml. of pyridine is heated at the refluxtemperature for six hours. The solution is cooled, diluted with 50 ml.of water and extracted with three 50 ml. portions of chloroform. Thecombined chloroform extracts are washed successively with 100 ml. ofdilute hydrochloric acid, 100 ml. of 10% sodium bicarbonate solution,and two 100 ml. portions of water. After drying over anhydrous magnesiumsulfate the chloroform is evaporated leaving a residue of crude3a-acetoxy-16-methyl-9(11),16- pregnadiene-20-one,

at 251 m A%=114 EXAMPLE 6 Soc-Acetoxy-l 6-Methyl-9 (11,16-Pregnadien-20-One To a stirred suspension of 13.9 g. of anhydrouscadmium chloride and 0.705 g. of anhydrous cuprous chloride in 70.5 ml.of anhydrous ether under a nitrogen atmosphere is added over a 5-minuteperiod 46.75 ml. of 3 M methyl magnesium iodide in ether. The solutionis heated at the reflux temperature for 90 minutes to form the methylcadmium derivative. A solution of 6.42 g. of3a-acetoxy-9(11),16pregnadien-20-one in 275 ml. of anhydrous ether isthen added with stirring over 15 minutes, and the mixture is allowed tostir nineteen hours. A precipitate of the ZO-cadmium enol derivative of3aacetoxy 16a methyl 9(11),17(20)-pregnadiene forms. The suspension isfiltered through a fritted disc built into the vessel, the solids arewashed with ether (100 ml), and the solid is then resuspended in 200 ml.of benzene containing 5 ml. of dry pyridine. A solution of 47 ml. of0.383 M bromine in benzene is added and the mixture is stirred at roomtemperature for 4 hours. T o the reaction mixture is added 150 ml. of10% sodium bisulfite solution and sufiicient dilute hydrochloric acid todissolve all solids. The benzene phaseis separated, washed with 300 ml.of dilute hydrochloric acid, two 200 ml. portions of 10% sodiumbicarbonate and two 300 ml. of water. After drying over magnesiumsulfate, the benzene solution is evaporated. The residue on triturationwith ether deposited material decomposing at 180. The residue on boilingin 15 ml. of methanol and chilling, gives solid M.P. 124-130 (dec.). Agram of the latter material, comprising17-bromo-3a-acetoxy-16u-methyl-9( 1 1)-pregnen-20-one dissolved in 10ml. of dry pyridine is heated at the reflux temperature for six hours,then cooled, and diluted with 50 ml. of water. The resulting crystalsafter chilling are collected, washed and dried. The presence of 3macetoxy-16-methyl-9(11),16-pregnadien-20-one is shown by the ultravioletabsorption;

6 EXAMPLE 7 Preparation of 16ot-Methyl-3-Acet0xy-9U1 -Pregnen-20- One Toa suspension of 2.17 g. of cadmium chloride and 0.11 of cuprous chloridein 11 ml. of ether is added 7.3 ml. of 3 molar methylmagnesium iodide inether. The mixture is boiled under reflux under nitrogen for one andone-half hours. To the mixture is added a solution of 1 g. of3-acetoxy-9(11),16-pregnadien-20-one in 43 ml. of ether and the mixturerefluxed with stirring for 16 hours. After decomposition of the mixturein the usual manner and recrystallization of the crude product frompetroleum ether, there is obtained 0.8 g. of 16u-methyl-3-acetoxy-9(11)-pregnen-20-one, M.P. 146l4'8 C.

EXAMPLE 8 3ca-Pr0pionoxy-16-Methyl-9 (11 ,1 6 -Pregnadien-20-One To asolution of 10 g. of 3a-propionoxy-16a-methyl- 9(1l)-pregnen-20-one in100 ml. of chloroform at 510 is added 53.6 ml. of 0.964 M bromine inchloroform over a period of minutes. The solution is washed with ml. of10% sodium bicarbonate solution, and 200 ml. of water. After drying overmagnesium sulfate, the chloroform solution is evaporated to dryness togive a crystalline residue of 17m,21-dibromo-3a-propionoxy-16-methyl-9(11)-pregnen-20-one in essentially quantitative yield.

Three grams of the above dibromoketone is treated according to theprocedures described in Example 4 to produce 3ozpropionoxy-16-methyl-9(11),16-pregnadien- 20-one.

The starting compounds of our invention, the 3-hydroxy (oracyloxy)-16-alkyl-9(l1)-pregnen-20-ones are conveniently prepared fromthe known 3,11fl-dihydroxy pregnan-ZO-one or the 3-acylate thereof, bybrominating said 3,11,6-dihydroxy pregnan-ZO-one or the 3-ester thereofin the presence of a strong acid catalyst to obtain17,21-dibromo-3-hydroxy-9 (11)-pregnen-20-one or a 3-ester thereof;contacting the thus obtained 17,21-dibromo-3-hydroxy-(ll)-pregnen-20-one or 3-ester thereof with sodium iodide inrefluxing acetone to form 17-bromo-3- hydroxy-9(l1)-pregnen-20-one or3-ester thereof and contacting saidl7bromo-3-hydroxy-9(l1)-pregnen-20-one or 3-ester thereof with refluxingpyridine to obtain 3-hydroxy-9(11),16-pregnadien-20-one or thecorresponding S-ester thereof followed by treatment with methylmagnesium iodide in the presence of cuprous chloride thereby forming16a-methyl-3-acetoxy-9 1 1)-pregnen-20-one or the corresponding3-hydroxy compound. These procedures are described in more detail in anapplication of which one of the present inventors is co-inventor, SerialNo. 748,178, filed July 14, 1958, now US. Patent No. 3,013,031.

The products obtained according to the process of this invention, e.g.3-hydroxy (or acyloxy)-16-alkyl-9(1l), 16-pregnadien-20-one are usefulas intermediates in the preparation of steroids which have valuableanti-inflam matory activity, as for example, 9oz-fl1101O-11fi,17oz,21-trihydroxy-16ot-methyl-1,4-pregnadiene-3,20-dione. Thus, the products ofour invention, i.e., 3-hydroxy(or acetoxy)-16-methyl-9(11),16-pregnadien-20-one is contacted with alkaline hydrogenperoxide to produce 3-hydroxy-16,17-oxido-l6-methyl-9(11)-pregnen-20-one which is converted by hydrogenationunder acid conditions to a mixture of 3,17m-dihydroxy-16ot-methyl-9( 11)-pregnen-20-one and 3, 17a dihydroxy 16fi-methyl-9 (l1)-pregnen-20-onewhich mixture may be conveniently separated by chromatography andcrystallization into the respective 16a-methyl and 16fl-methyl isomer.The latter compounds are reacted'with bromine and chloroform to form21-bromo- 311,170: dihydroxy-16a-methyl-9(11)-pregnen-20-one and thecorresponding 16fi-methyl isomer which are reacted with sodium iodide inacetone to produce 21-iodo-3a,

17a-dihydroxy-16a-methylpregnan-20-one and the cor-- and 7 respondingl6fi-methyl isomer which are converted without isolation to2lacetoxy-3a,17a-dihydroxy-16u-methyl- 9(11)-pregnen-20-one and thecorresponding lfifl-methyl isomer by reaction with anhydrous potassiumacetate; these compounds are then reacted with chromium trioXide inpyridine to formZI-BCEtOXY-17oc-hYdIOXY-16amethyl-9(11)-pregnene-3,20-dione and thecorresponding 16B-methyl isomer. The latter compounds are then convertedto the corresponding l,4,9(l1)-pregnatriene com.- pounds by contactingthem with selenium dioxide or the dehydrogenating activity ofmicroorganisms; for example, Nocardia asteroides (ATCC 9970). Theproducts thus obtained are l7ot,2l,-dihydroxy.-16m-methyl-1,4,9(1l)pregnatriene-3,20-dione and the corresponding 16B-methyl isomer whichare acetylated on reaction with acetic anhydride and pyridine to givethe corresponding 21-aceto2ry compounds; the latter compounds arereacted with hypobromus acid to produce 9a-bromo-21-acetoxy-l1,8,l7a-

dihydrQXy-IGa-methyl-I,4 pregnadieneE3,ZO-dione and the 7 corresponding16 8-methyl isomer which are reacted with anhydrous potassium acetate inethanol to produce 21- acetoxy 9(11)epoxy-17whydroxy-1Gwmethyl-IA-pregnadiene-3,20-dione and thecorresponding ids-methyl isomer. These 9(11)-epoxy compounds are thenreacted with hydrogen fluoride in tetrahydrofuran to produce 90:- fluoro21 acetoxy 11fi,17a-dihydroxy-16a-n1ethyl 1,4- pregnadiene-3,20-dioneand the corresponding lfifi-rnethyl isomer; these compounds are reactedwith a hydrolyzing agent to form 9a fluoro 11 5,17 u,21.-tIihYdIOXY-lGocmethyl-1,4-pregnadiene-3,20-dione and the corresponding16,6-methy1 isomer.

Various changes and modifications may be made carrying out the presentinvention without departing from the spirit and scope thereof. Insofaras these changes and modifications are within the purview of the annexedclaims, they are to be considered as part of our invention We claim:

1. The process which comprises contacting a member selected from thegroup consisting of compounds of the formulas: I

on WCO v I wherein R issa member selected from the group consisting ofhydrogen and lower alkanoyl, R is a lower alkyl substituent, and R is alower alkanoyl .substituent, with brominel'in azmolar ratio of fromabout l-Z moles ofbromine per mole of steroid compound at atemperature b8 w a a of from about 30 C. to 100 C., thereby forming a 17- bromosteroid of the formula:

(llHgR 0 0 New wherein R is a member selected from the group consistingof hydrogen and lower alkanoyl, X is a halogen, and R is a lower alkylsubstituent, with bromine in a molar ratio of from about 1-2 moles ofbromine per mole of steroid compound at a temperature of from about 30C. to 100 C. to form a' 17-bromo steroid of the formula:

CH2R1 Wh 03 U wherein R is a member selected from the group consistingof. hydrogen and acyl, vR is hydrogen, and R is a lower 'alkylsubstituent.

3, The processwhich comprises contacting a member 7 selected from thegroup consisting of magnesium ZG-enol derivatives of the formula:

C-OMgX is a lower alkyl substituent, with bromine in 'a molar ratio offrom about 1?. moles of bromine per mole of steroid compound at atemperature of from about 30 C. to 100 C. to form a 17-bromo steroid ofthe formula:

wherein R is a member selected from the group consisting of hydrogen andacyl, R is hydrogen, and R is a lower alkyl substituent.

4. The process which comprises contacting a member selected from thegroup consisting of compounds of the formula:

wherein R is a member selected from the group consisting of hydrogen andlower alkanoyl, and R is a lower alkyl substituent, with bromine in amolar ratio of from about 1-2 moles bromine per mole of steroid compoundat a temperature of from about 30 C. to 100 C. to introduce bromine intothe 17-position and form a 17-bromo steroid of the formula:

CHzRr 10 wherein R is a member selected from the group consisting ofhydrogen and acyl, R is a member selected from the group consisting ofhydrogen and bromine, and R is a lower alkyl substituent.

5. The process which comprises contacting a 17,21-dibromo-9(1l)-pregnene compound of the formula:

wherein R is a member selected from the group consisting of hydrogenandlower alkanoyl, R is bromine, and R is a lower alkyl substituent, withsodium iodide to form a 9(11),1-6-pregnadiene compound of the formula:

GHnRi =0 I "Br r wherein R is a member selected from the group consist-

1. THE PRICESS WHICH COMPRISES CONTACTING A MEMBER SELECTED FROM THEGROUP CONSISTING OF COMPOUNDS OF THE FORMULAS: